Significant improvements in the primary success rate of various medical and surgical treatments of atherosclerotic disease have been made in the last few years. Yet recurring failures continue in 30 to 50% of the patients after balloon angioplasty, bypass surgery, and endarterectomy because of late restenosis of the treated vessel. The restenosis is a result of a complex series of fibroproliferative responses to the vascular injury that results in vascular smooth muscle cell (VSMC) proliferation, migration, neointimal accumulation, and secretion of extracellular proteins Microtubules are likely involved in controlling or moderating critical intracellular mechanisms necessary for the VSMC fibroproliferative response. We hypothesize that stabilizing microtubules with taxol or other agents may disrupt the mechanisms involved in the fibroproliferative response of the smooth muscle cells and therefore limit the cellular response to injury. We found that taxol, a microtubule stabilizing agent, inhibited VSMC proliferation, migration, and invasion in vitro. In vivo, taxol prevented neointimal VSMC accumulation in the rat carotid artery after balloon dilation and endothelial denudation injury. We found that taxol treatment of the rats significantly inhibited proliferation of medial and neointimal smooth muscle cells after balloon angioplasty. An en face view of the carotid artery 4 days after injury reveals the initial cells migrating from the media across the internal elastic lamina to form a neointima. Taxol treatment significantly inhibited the migration/invasion of smooth muscle cells in this assay. The taxol concentrations necessary for inhibiting neointimal formation were 100 to 1000 times lower than the levels measured for the treatment of tumors in comparable assays. We subsequently have found that another microtubule stabilizing agent, D2O (heavy water) also inhibited VSMC proliferation, migration, and invasion in vitro and neointimal formation in vivo. These experiments suggest that taxol, D2O, or other pharmacologic agents that stabilize microtubules may have therapeutic value in preventing human restenosis after balloon angioplasty, bypass surgery, and endarterectomy.